Tolterodine is used in the treatment of hyperactive bladder, and widely distributed in the market in the form of an oral formulation. Currently, a commercially available tolterodine oral formulation mainly uses tolterodine tartrate as an active ingredient.
Meanwhile, regarding a transdermal absorption-type formulation containing tolterodine, there have been attempts to develop a patch by various methods until now (Patent Documents 1-4). A patch has advantages, for example, in that a constant blood drug concentration can be maintained and the administration can easily be discontinued by peeling off the patch when a side effect occurs. Further, while an oral formulation requires a liquid such as water at the time of administration and thus has a possibility of producing an adverse effect on the treatment due to increase of urge to urinate, a patch does not increase urge to urinate and thus is advantageous to drug compliance of a patient.
Generally, in a transdermal absorption-type formulation, it is known that higher transdermal absorbability is achieved when a free base is used as compared to an acid addition salt. Therefore, regarding tolterodine, mainly a patch using a free base has been reported (Patent Documents 2-4).
However, if an inappropriate base ingredient is selected for a patch using a tolterodine free base, tolterodine may react with the base ingredient and thereby may be decomposed. As a result, the content of the active ingredient may decrease during storage, a degradation product may be produced, and thereby an adverse effect may occur in the formulation stability. Namely, if a tolterodine free base is selected as the active ingredient, an appropriate base ingredient must be selected so as not to produce an adverse effect in the active ingredient stability.
The patch containing a tolterodine free base disclosed in the above Patent Documents 2-4 mainly uses an acrylic adhesive. However, when tolterodine is mixed with an acrylic adhesive, the content of the active ingredient decreases during storage, and a degradation product is readily formed. Namely, in view of the formulation stability, a patch containing an acrylic adhesive as a base ingredient is insufficient.
Also, a tolterodine-containing patch has a problem with skin irritation. In this respect, the present inventors have found that a transdermal permeation rate of tolterodine (flux: μg/cm2/hr) is correlated with the skin irritation of a patch. Therefore, in the preparation of a tolterodine-containing patch, the present inventors have found that a good balance between drug efficacy and safety can be achieved by adjusting the transfer rate of the drug from a formulation to a skin in an appropriate range. These properties of tolterodine are not described nor suggested in the above related art documents, and are newly found by the present inventors' earnest studies.